ReviewMolecular mechanisms for activity-regulated protein synthesis in the synapto-dendritic compartment
Introduction
Synapses are the pre-eminent mediators of information processing in the nervous system. These remarkable structures utilize a host of morphological and biochemical strategies to accomplish efficient neurotransmission. Synapses also possess a rich capacity for use-dependent modification. Such plasticity is crucial for information processing and storage in the brain. These modifications take place over a vast range of time frames. For example, paired-pulse facilitation is initiated in milliseconds and decays rapidly. The early stages of long-term potentiation (LTP) or long-term depression (LTD) are initiated within seconds to minutes of appropriate synaptic stimulation and (in the absence of new protein synthesis) decay within 1–2 h. Finally, an important class of synaptic modifications can last for days to years — and perhaps even for the life of the individual [1]. These long-term changes in synaptic strength are thought to be the basis for memory storage 2, 3.
Although shorter-term synaptic modifications may be brought about by covalent modification of existing proteins, long-lasting changes require new protein synthesis 4, 5, 6. These new polypeptides undoubtedly play a key role in synaptic modification; some of them are likely to be incorporated into the synapses, whereas others may be necessary for transmitting signals to the soma 7, 8.
Neurons employ at least three strategies for the activity-dependent regulation of protein synthesis and targeting. First, some proteins are translated in the soma from newly transcribed mRNAs. For example, transcription factors such as CREB (cAMP-response-element-binding protein) and C/EBP (CCAAT enhancer binding protein) are activated in response to particular forms of synaptic stimulation [9]. CREB also plays a key role in the formation of long-term memories in fruit flies [10]. The processes by which such remotely synthesized proteins are delivered to the appropriate synapses are not yet fully understood, but seem likely to involve the creation of ‘tags’ at the activated synapses [11]. Second, newly transcribed mRNAs may be transported to activated synapses, where they are thought to be translated. This mechanism has been recently described for Arc, an immediate-early gene whose transcription is tightly regulated by synaptic activity [12••]. The shunting of mRNAs into the dendritic region is presumably accompanied by concomitant protein synthesis upon their arrival at the appropriate target synaptic region.
A third strategy for achieving activity-dependent regulation of protein synthesis and targeting — which is the focus of this review — is by the regulated translation of mRNAs localized at synapses. This mode is suggested by the observations that dendritic shafts contain polyribosomes, tRNAs, initiation factors, and specific mRNAs 13, 14, 15. As polyribosomes are frequently found at the base of synaptic spines, they may service restricted domains of the synapto-dendritic compartment — even individual synapses. Although several mRNAs are known to be localized to dendrites in situ, including those encoding microtubule-associated protein 2 (MAP2), Arc, fragile X mental retardation protein (FMRP), and the α subunit of calcium/calmodulin-dependent protein kinase II (α-CaMKII), the total dendritic complement is likely to be far richer. For example, a host of other mRNAs have been identified in the dendrites of cultured neurons 8, 16.
Section snippets
Local mRNA translation at synapses
Recent work has established a direct link between local mRNA translation and synaptic plasticity. In an elegant set of experiments, Kandel and co-workers [7] have shown that protein synthesis inhibitors, when selectively applied to the synapse, block long-lasting, long-term facilitation (L-LTF) in cultured Aplysia neurons. In vertebrates, dendritic protein synthesis seems likely to play a role in long-lasting hippocampal L-LTP as well. For example, high-frequency stimulation of hippocampal
Cellular and molecular requirements for local mRNA translation
For mRNA translation to occur at the synapse, the neuron must first target and transport specific mRNAs to the dendrite, then dock or store them in the synapto-dendritic domain, and finally trigger their translation following appropriate synaptic stimulation. mRNA targeting to synapses has been the subject of several recent reviews 23, 24, 25. The targeting signals can reside in either the 3′-untranslated region (UTR) [26] or the 5′ region [27]. Steward and colleagues 12••, 28 have shown that
Polyadenylation and control of translation during early development
The oocytes of both vertebrates and invertebrates contain a stockpile of dormant mRNAs that are transcribed during the very long period of oogenesis and then cached in the cytoplasm. Some of these dormant mRNAs have relatively short poly(A) tails; these are usually fewer than ∼20–40 nucleotides in length. After oogenesis, when the oocyte resumes meiosis (an event known as oocyte maturation), a subset of these mRNAs undergoes poly(A) tail elongation and translational activation 41, 42, 43, 44, 45
CPEB-dependent mRNA translation in the brain
CPEB is highly expressed in the brain [38••], where it is found in the cell body and dendritic layers of the hippocampus, as well in the cerebral cortex and other regions. This sequence-specific mRNA-binding protein is localized at synapses in cultured hippocampal pyramidal neurons and is a component of the postsynaptic density (PSD) fractions isolated from adult CNS [38••]. The 3′UTR of α-CaMKII mRNA contains two CPEs within 100 nucleotides of the hexanucleotide sequence. CPEB binds this 3′UTR
Conclusions
After a long period of anticipation, a role for local mRNA translation in synaptic plasticity has recently been established. Several pathways have now been shown to trigger such translation, including mGluR-, NMDAR-, and neurotrophin-mediated stimulation. One molecular mechanism that is likely to regulate at least some dendritic protein synthesis is CPEB-mediated cytoplasmic polyadenylation. The task for the future will be to illuminate the links between specific kinds of synaptic activation
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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